Cellular therapy is emerging as a promising new approach to the treatment of disorders in which cells have been lost or have become dysfunctional. Unfortunately, the cells and tissues needed to conduct these therapies are in short supply. Before cellular therapy can be routinely and successfully employed in the clinic, new methods need to be developed that can generate large numbers of cells suitable for transplantation. Our objective is to address this clinical need by investigating the potential of inducing stem cells to differentiate into the desired cell type. We hypothesize that purified hematopoietic stem cells can be induced to differentiate into cells of an endocrine lineage. Our specific aims are to examine the effect on the differentiation of hematopoietic stem cells of 1) genetically modifying them to express proendocrine transcription factors and 2) co-culturing them with carrier embryonic stem cells that have been driven to adopt an endocrine fate. We will determine how these manipulations affect which pancreatic endocrine genes are turned on and the nature and timing of their expression. We expect to be able to identify fully differentiated cells that express the phenotype and physiology of each of the four islet cell types, including beta cells. Our long term goal is to establish an experimental system for the study of stem cell differentiation and transdifferentiation, and to develop methods for the generation of large numbers of cells that can be used for cellular therapies for type 1 diabetes and other disorders of the pancreas.